AAD-2004, a potent spin trapping molecule and microsomal prostaglandin E synthase-1 inhibitor, shows safety and efficacy in a mouse model of ALS

While free radicals and inflammation constitute major routes of neuronal injury occurring in neurodegenerative diseases, neither antioxidants nor nonsteroidal anti-inflammatory drugs (NSAIDs) have shown significant efficacy in human clinical trials. To explore the possibility that concurrent blockade of free radicals and PGE2-mediated inflammation might constitute a safe and effective therapeutic approach to certain neurodegenerative diseases, we have developed 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobezoic acid (AAD-2004) as a derivative of aspirin. AAD-2004 completely removed free radicals at 50 nM as a potent spin trapping molecule and inhibited microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 230 nM. Oral administration of AAD-2004 blocked free radical formation, PGE2 formation, and microglial activation in the spinal motor neurons of SOD1G93A mice. As a consequence, AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span. In these assays, AAD-2004 was superior to ibuprofen or riluzole. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in SOD1G93A mice. Targeting both mPGES-1 and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases

Heterogeneous popularity of metabolic reactions from evolution

The composition of cellular metabolism is different across species. Empirical data reveal that bacterial species contain similar numbers of metabolic reactions but that the cross-species popularity of reactions is so heterogenous that some reactions are found in all the species while others are in just few species, characterized by a power-law distribution with the exponent one. Introducing an evolutionary model concretizing the stochastic recruitment of chemical reactions into the metabolism of different species at different times and their inheritance to descendants, we demonstrate that the exponential growth of the number of species containing a reaction and the saturated recruitment rate of brand-new reactions lead to the empirically identified power-law popularity distribution. Furthermore, the structural characteristics of metabolic networks and the species' phylogeny in our simulations agree well with empirical observations.Comment: Main: 5 pages, 4 figures, Supplemental Material: 4 pages, 6 figure

Site Response Analysis Using Forced-Vibration Tests on Hydraulic-Filled Soil Deposit

Forced vibration tests and detailed site characterization were performed at a geotechnical experimental site in Yong-jong Island where Inchon International Airport being constructed. The vibratory motions generated by the combination of hydraulic hammer compaction and dynamic compaction were monitored by 3-component velocity transducers in the down hole array as well as on the ground surface. Spectral analyses of the recorded vibratory motions were performed to evaluate the resonant frequencies of the experimental site. The linear analysis and simplified method were also performed to evaluate the resonant frequencies of the experimental site based on the results of detailed site investigation. The resonant frequencies of the experimental site evaluated by spectral analyses based on forced vibration tests were in good agreement with those of the linear analysis and the simplified method